DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 84-103 are pending and under examination. Claims 1-83 are canceled. Claims 84-86 are amended.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/25/26 has been entered.
Priority
The instant application 17/816,198 filed on 7/29/22 is a CON of PCT/US21/16089 filed on 2/1/21 and claims domestic priority to provisional applications 62/988,859 filed 3/12/20; 62/987,232 filed 3/9/20; and 62/968,847 filed 1/31/20. The priority date is determined to be 1/31/20.
Response to Arguments
Applicant’s arguments, see pages 7-12, filed 3/25/26, with respect to the rejections of claims 84-103 under 35 USC 103 and nonstatutory double patenting have been fully considered and are found persuasive. Therefore, the rejections documented in the Final mailed 2/9/26 have been withdrawn. However, upon further consideration, new grounds of rejections necessitated by claim amendments are made in this Non-Final Office Action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 84-89, 91-97, and 102-103 are rejected under 35 U.S.C. 103 as being unpatentable over Raymond (2010; WO 2010/030683 A1; FOR citation 1 in IDS filed on 4/3/24) in view of Richard (2016; US 2016/0002720 Al; USPGPub citation 070 in IDS filed 12/1/22).
This new 103 rejection is necessitated by claim amendments filed 3/25/26.
(i) Raymond teaches limitations relevant to claims 84-89, 91-97, and 102-103.
Relevant to claim 84, Raymond teaches "EXAMPLE 4: This example describes solution-based capture using indirect capture via chimeric capture oligos with a gene-specific region and a region that hybridizes to a universal biotinylated adaptor oligo, with a set of indirect oligos that are specific for a set of 5 genes of interest" (page 78, lines 1-5). The method is displayed in Raymond Figure 5.
Further relevant to claim 84, Raymond teaches "double-stranded nucleic acid fragments 10 are combined with the first 20 and second 30 stem-loop linker oligonucleotides in a ligation reaction" (page 13, lines 23-24).
The Raymond "double-stranded nucleic acid fragments” are equivalent to the instant template nucleic acid molecule.
Further relevant to claim 84, Raymond teaches a "chimeric capture probe 200, 200' with a first region 202 that hybridizes to a target nucleic acid sequence 10, 10' in the library" (page 78, lines 23-25).
The Raymond "chimeric capture probe" is equivalent to the instant first/second bridge probe.
Further relevant to claim 84, Raymond teaches "As shown in FIGURE 5, in another embodiment of the method of this aspect of the invention, the capture probes 200 comprise a target-sequence specific binding region 202, 202' and a capture reagent binding region 204 that hybridizes to a universal adaptor oligonucleotide 300 comprising a moiety 310 that binds to a capture reagent 400" (page 19, lines 32- 33 continued to page 20, lines 1-2).
The Raymond "capture reagent binding region… that hybridizes to a universal adaptor oligonucleotide" is equivalent to the instant first/second adaptor landing sequence… configured to hybridize to a… binding sequence of the universal anchor probe.
Further relevant to claim 84, Raymond page 18 teaches embodiments wherein “more than one chimeric capture probe should be used,” including sets of target capture probes that include “multiple capture probes that overlap the target sequence”, and those that “are typically designed to hybridize to target sequences spaced apart”.
Relevant to claims 85-86, Raymond teaches "double-stranded nucleic acid fragments 10 are combined with the first 20 and second 30 stem-loop linker oligonucleotides in a ligation reaction" (page 13, lines 23-24).
Relevant to claim 87, Raymond teaches "As shown in FIGURE 5, an alternative approach for target gene enrichment of a genomic library is to use indirect capture by generating a chimeric capture probe 200, 200' with a first region 202 that hybridizes to a target nucleic acid sequence 10, 10' in the library and a second region 204 that hybridizes to a universal biotinylated oligo 300, mixing the chimeric oligo, the universal biotinylated oligo and the library containing a plurality of nucleic acid molecules 50 under hybridizing conditions to form a tri-molecular complex (i.e., 50/200/300)…" (page 78, lines 22-28).
Relevant to claim 88, Raymond teaches “The use of 5' and 3' stem-loop linkers is a key element of the library construction since they provide universal primer binding sites for subsequent PCR and may contain primer binding sites/anchors for sequencing cluster generation and they can be used to introduce bar-codes for sample multiplexing” (page 35, lines 19-22).
Relevant to claim 91, Raymond teaches "In some embodiments, at least one of the stem-loop linker oligonucleotides (e.g., either 20 or 30) further comprises one or more molecular bar code sequences" (page 13, lines 13-14).
Relevant to claims 92-93, Raymond teaches "The universal adaptor oligonucleotide 300 is present at an equal concentration as the capture probes 200, and hybridize to the capture reagent binding region 204. The moiety 310 (e.g., biotin) attached to the universal oligo adaptor 300 is then contacted with a capture reagent 400 (e.g., a magnetic bead) having a binding region 410 (e.g., streptavidin coating) and the complex is pulled out of solution with a sorting device 500 (e.g., a magnet) that binds to the capture reagent 400" (page 20, lines 6-11).
Relevant to claim 94, Raymond Figure 6 teaches that the probe hybridizations occur before the addition of the capture reagent/generation of complexes and subsequent complex isolation, thus teaching that the universal anchor probe is not attached to a solid support during the bridge probe hybridizations.
Relevant to claims 95-97, Raymond teaches "The universal adaptor oligonucleotide 300 is present at an equal concentration as the capture probes 200, and hybridize to the capture reagent binding region 204. The moiety 310 (e.g., biotin) attached to the universal oligo adaptor 300 is then contacted with a capture reagent 400 (e.g., a magnetic bead) having a binding region 410 (e.g., streptavidin coating) and the complex is pulled out of solution with a sorting device 500 (e.g., a magnet) that binds to the capture reagent 400" (page 20, lines 6-11).
Relevant to claims 102-103, in addition to the above teachings, Raymond Abstract teaches "The invention provides compositions and methods for generating a target enriched, sequencing ready library for resequencing at least one target region of interest from a nucleic acid containing sample."
Taken as a whole, Raymond discloses both a kit (claim 102) and a composition (claim 103) that performs the method and fulfills the instant claims 102-103 limitations.
(ii) Raymond is silent to specifics regarding linker sequences (claim 84). However, this limitation was known in the prior art and taught by Richard.
Richard Abstract teaches “Methods and compositions are provided for enriching for target sequences from a population of nucleic acids, that includes combining in solution, a population of nucleic acids and a target isolation probe wherein the target isolation probe includes an affinity binding domain; permitting a single stranded region of the target isolation probe to hybridize to all or a portion of a target sequence in the population of nucleic acids; selectively immobilizing the hybridized nucleic acids from the population containing the target sequences by associating the target isolation probe with a capture domain and removing unbound material; and removing from the 3' end of the target sequence, a non-target sequence by means of one or more 3' single strand specific exonucleases. Target enrichment may be used to detect variations in nucleotide sequence for detecting phenotypic changes related to health or disease.”
Relevant to claim 84, Richard teaches “The target isolation probe can include modifications on either or both the 3' and 5' ends to prevent exonuclease degradation, ligation, and/or polymerase extension. Modifications may include one or more of the following: … carbon linkers” (paragraph 0018).
(iii) Although Raymond does not explicitly teach the Richard linker sequence, it would have been prima facie obvious to the skilled artisan. It is noted that Raymond and Richard are analogous disclosures in the instant nucleic acid capture methodology.
The skilled artisan would have been motivated to combine the analogous art. The skilled artisan would have been motivated to include the Richard linker sequence within the Raymond capture probes because Richard teaches that probe-inclusion of linker sequences prevents “exonuclease degradation, ligation, and/or polymerase extension.” The skilled artisan would have a reasonable expectation of success based on the disclosures of Raymond in view of Richard, as discussed in the preceding paragraphs.
Claims 90 and 98-101 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Raymond (2010; WO 2010/030683 A1; FOR citation 1 in IDS filed on 4/3/24) in view of Richard (2016; US 2016/0002720 Al; USPGPub citation 070 in IDS filed 12/1/22), as applied to claims 84-89, 91-97, and 102-103 above, and further in view of Battersby et al. (2014; WO 2014/015098 A1; FOR citation 3 in IDS filed on 4/3/24).
The teachings of Raymond in view of Richard are applied to instantly rejected claims 90 and 98-101 as they were previously applied to claims 84-89, 91-97, and 102-103 as rendering obvious a method, kit, and composition.
Raymond in view of Richard is silent to specifics regarding spacers (claim 90) and methylation assays (claims 98-101). However, these limitations were known in the prior art and taught by Battersby et al.
Relevant to claim 90, Battersby et al. teaches "Labeled detection primers can be prepared by incorporation of or conjugation to a detectable moiety. Labels can be attached directly to the nucleic acid sequence or indirectly (e.g., through a linker). Linkers or spacer arms of various lengths are known in the art and are commercially available, and can be selected to reduce steric hindrance, or to confer other useful or desired properties to the resulting labeled molecules [citation]" (paragraph 0078).
Relevant to claims 98-99, Battersby et al. teaches “In some embodiments, target nucleic acids may be non-randomly fragmented. In embodiments wherein the nucleic acid targets are DNA, non-random fragmentation can be accomplished through treatment with restriction enzymes to completely digest or partially digest a DNA sample. The restriction enzymes can be methylation-sensing or non-sensing restriction enzymes” (paragraph 0063).
This teaching reads on claim 98 further comprising treating the template nucleic acid molecule with a methylation assay reagent… thereby generating a treated template nucleic acid molecule; and claim 99 wherein the methylation reagent is… an enzyme that modifies methylated cytosines.
Relevant to claim 100, Raymond Figure 3, step 670 of “PCR Amplify” reads on claim 100 further comprising amplifying the treated nucleic acid molecule thereby generating amplified products.
Relevant to claim 101, Raymond Figure 3, step 680 of “Sequence” reads on claim 101 further comprising sequencing the amplified products.
Although Raymond in view of Richard does not explicitly teach the Battersby et al. spacers or methylation assay, it would have been prima facie obvious to the skilled artisan. Raymond, Richard, and Battersby et al. are analogous disclosures in the instant nucleic acid capture methodology.
The skilled artisan would have been motivated to combine the analogous art. The skilled artisan would have been motivated to include the Battersby et al. spacers within the modified-Raymond methodology because Battersby et al. teaches “Linkers or spacer arms of various lengths are known in the art and are commercially available, and can be selected to reduce steric hindrance, or to confer other useful or desired properties to the resulting labeled molecules [citation]" (paragraph 0078).
The skilled artisan would have also been motivated to include the Battersby et al. methylation assays within the modified-Raymond methodology because Battersby et al. teaches "Particular sequencing methodologies that may benefit from the normalization methods described here include cyclic reversible termination and sequencing by ligation. Particular applications to which the various sequencing methodologies may be applied to include de novo genome sequencing, RNA-seq, and genome-wide profiling of epigenetic marks and chromatin structure (ChIP-seq; methyl-seq; DNAse-seq)" (paragraph 0063).
Thus, the skilled artisan would have been motivated by the spacer-mediated reduction of steric hindrance/conferral of desired properties and the genome-wide epigenetic profiling applications. The skilled artisan would have a reasonable expectation of success based on the disclosures of Raymond in view of Richard, and further in view of Battersby, as discussed in the preceding paragraphs.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 84-103 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 170, 172-182, and 190-192 of copending Application No. 17/326,475 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to forming a nucleic acid complex for the detection of a target nucleic acid.
This new nonstatutory double patenting rejection is necessitated by claim amendments filed 3/25/26.
The copending claims do not teach a single claim that includes all of the limitations of instant claim 84+ in a single claim. However, it would have been prima facie obvious to the skilled artisan to have modified any one of the copending claims so as to have applied it to the formation of a nucleic acid detection complex since this is a specifically named embodiment of the invention in copending claims 170+. Since all the claims in the copending application are directed toward the formation of this nucleic acid complex, it would have been obvious to combine the methods of the copending claims to achieve the predictable outcome of forming a nucleic acid complex.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 84-103 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/839,303 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to forming a nucleic acid complex for the detection of a target nucleic acid.
This new nonstatutory double patenting rejection is necessitated by claim amendments filed 3/25/26.
The copending claims do not teach a single claim that includes all of the limitations of instant claim 84+ in a single claim. However, it would have been prima facie obvious to the skilled artisan to have modified any one of the copending claims so as to have applied it to the formation of a nucleic acid detection complex since this is a specifically named embodiment of the invention in copending claims 1+. Since all the claims in the copending application are directed toward the formation of this nucleic acid complex, it would have been obvious to combine the methods of the copending claims to achieve the predictable outcome of forming a nucleic acid complex.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah J Kennedy whose telephone number is (571)272-1816. The examiner can normally be reached Monday - Friday 8a - 5p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Winston Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
Prosecution Insights